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Title:New methodologies and approaches to reaction discovery in transition metal catalysis
Author(s):Robbins, Daniel
Director of Research:Hartwig, John F.
Doctoral Committee Chair(s):Hartwig, John F.
Doctoral Committee Member(s):Burke, Martin D.; Hergenrother, Paul J.; Sweedler, Jonathan V.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Organometallic chemistry
C-H activation
Reaction discovery
Abstract:A series of synthetic methods have been developed based upon iridium-catalyzed borylation of aromatic and heteroaromatic C-H bonds. A general, one-pot method for alkylation of arenes with the site-selectivity controlled by steric effects as opposed to electronic effects via Ir-catalyzed C-H borylation followed by Pd- or Ni-catalyzed coupling with allylic, benzylic or unactivated alkyl electrophiles has been developed. Simple palladium catalysts enable the coupling of aryl boronate esters formed from iridium-catalyzed C-H borylation to be coupled with various allylic halides, allylic carboxylates and benzylic halides. Nickel catalysts bearing diamine or phenanthroline- based ligands have been used to couple these aryl boronate esters with primary and secondary, unactivated alkyl halides. Meta-selective alkylation of a broad scope of arenes with various electronic properties and functional groups, including aryl halides, esters, amides, ethers and ketones, has been demonstrated with good yield. This methodology has also been used to perform a one-pot total synthesis of elemicin, a natural product with potential biological activity, and a formal synthesis of an HIV drug candidate. In another study, a new approach to Suzuki-Miyaura coupling of potentially unstable organoboronates was developed. Biaryls in which one or more of the aryl rings are heteroarenes or fluorinated arenes are found widely in medicinal chemistry and materials science, but are challenging to prepare by Suzuki-Miyaura coupling because of the instability of the corresponding boronic acids. A strategy to prepare and use in situ or as isolated material for cross coupling the pinacolboronate esters of unstable boronic acids has been developed. These pinacol boronates are synthesized using iridium-catalyzed C-H borylation, a direct and mild method for borylation, and are stable indefinitely in isolated form on the benchtop. The corresponding boronic acids require cold, anaerobic storage. These boronate esters can also be used in situ for Suzuki coupling with aryl halides with easily accessible palladium catalysts in a one-pot procedure. Mechanistic studies revealed the features of the pinacolboronates that enable these cross couplings to occur in high yields. Protodeborylation of the pinacol boronate is slow, and the transmetallation of the pinacol boronate with an intermediate palladium hydroxide complex occurs rapidly without generation of the boronic acid. This C-H borylation and cross coupling sequence can be conducted on small or large scale and does not require the use of a glovebox. Because of the importance of these substructures, this methodology should find many applications. In a third study focused on iridium-catalyzed C-H borylation, a method for site-selective borylation of nitrogen-containing heterocycles was developed. Selective methods for the functionalization of indoles and other nitrogen heterocycles would provide access to the core structures of many natural products and pharmaceuticals. Although there are many methods and strategies for the synthesis of substituted indoles or functionalization of the azole ring, strategies for the selective functionalization of the benzo-fused portion of the indole skeleton, particularly the 7-position, are less common. We report a one-pot, iridium-catalyzed, silyl-directed C−H borylation of indoles at the 7-position. This process occurs in high yield with a variety of substituted indoles, and conversions of the 7-borylindole products to 7-aryl-, 7-cinnamyl-, and 7-haloindoles are demonstrated. The Ir-catalyzed, silyl-directed C−H borylation also occurs with several other nitrogen heterocycles, including carbazole, phenothiazines, and tetrahydroquinoline. The utility of this methodology is highlighted by the one-pot synthesis of a member of the pyrrolophenanthridone class of alkaloid natural products. In another set of studies, a new approach to the use of high-throughput, multidimensional screening of transition metal catalysts and organic substrates was developed. Although high-throughput methods for catalyst discovery that would mirror related approaches for the discovery of medicinally active compounds have been the focus of much attention over the past fifteen years, these methods have not been sufficiently general or accessible to typical synthetic laboratories to be adopted widely. A method to evaluate a broad range of catalysts for potential coupling reactions using simple laboratory equipment has been developed. Specifically, an array of catalysts and ligands with a diverse mixture of substrates was screened, and then mass spectrometry was utilized to identify coupling products that by design exceed the mass of any single substrate. Using this method, we have discovered a copper catalyzed alkyne hydroamination reaction and two nickel-catalyzed hydroarylation reactions, all displaying excellent functional group tolerance.
Issue Date:2012-09-18
Rights Information:Copyright 2012 Daniel Robbins
Date Available in IDEALS:2012-09-18
Date Deposited:2012-08

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